The most promising approach appears at this time to be direct manipulation of the lateral hypothalamus, either by stereotaxically placed electrolytic lesions in it or its afferent pathways (ventral tegmental area, median forebrain bundle) or by local injection of HDA60. The variability of results which have been obtained with efforts to affect the lateral hypothalamus are due to a considerable or more probably to a major extent to problems with stereotaxic electrode and cannula placement in the monkey. This is concluded from the histology of a significant number of brains which have been studied and which have shown that with identical coordinates, differences of several millimeters occur in the A. P. plane in location of electrode tips. We have developed a method for performing positive contrast ventriculography in the monkey in a stereotaxic instrument in both A. P. and lateral planes and are now applying this to all experiments. Proposed studies: Since, as noted, the number of animals in which pronounced dependence has been obtained and significant depression of this dependence by lateral hypothalamic lesions is still small it will be necessary to increase these numbers to 6 or more animals in each category. Thus, at least 3 more monkeys with electrolytic and 3 more with HDA60 lesions of the lateral hypothalamic area will be needed. Simulation studies of the hypothalamus in morphine dependent monkeys with a total of 6 monkeys to be tested. In 3 of these, electrodes will be introduced into the ventromedial nucleus while in the other 3 the electrodes will be placed in the lateral hypothalamus. The working hypothesis is that stimulation of the lateral hypothalamus should result in increased self-administration of morphine while stimulation of the ventromedial nucleus should decrease or suppress this activity. As described in the Detailed Report, in one monkey a complete cessation of self-administration of morphine resulted from such stimulation and persisted without any sign of relapse. Study of the effects of local injection of HDA60 and 5-6 DHTA into the lateral hypothalamus of dependent monkeys. This work has been initiated recently but it is too early to be able to draw conclusions regarding effectiveness.